title: Doxorubicin-loaded polymeric micelle overcomes multidrug resistance of cancer by double-targeting folate receptor and early endosomal pH.
abstract: An optimized, pH-sensitive mixed-micelle system conjugated with folic acid is prepared in order to challenge multidrug resistance (MDR) in cancers. The micelles are composed of poly(histidine (His)-co-phenylalanine (Phe))-b-poly(ethylene glycol) (PEG) and poly(L-lactic acid) (PLLA)-b-PEG-folate. Core-forming, pH-sensitive hydrophobic blocks of poly(His-co-Phe) of varying composition are synthesized. The pH sensitivity of the micelles is controlled by the copolymer composition and is fine tuned to early endosomal pH by blending PLLA(3K)-b-PEG(2K)-folate in the presence of a basic anticancer drug, doxorubicin (DOX). In vitro tests are conducted against both wild-type (A2780) and DOX-resistant ovarian carcinoma cell lines. A mixed-micelle system composed of poly(His-co-Phe (16 mole%))-b-PEG (80 wt%) and PLLA-b-PEG-folate (20 wt%) is selected to target early endosomal pH. DOX-loaded micelles effectively kill both wild-type sensitive (A2780) and DOX-resistant ovarian MDR cancer-cell lines (A2780/DOX(R)) through an instantaneous high dose of DOX in the cytosol, which results from active internalization, accelerated DOX release triggered by endosomal pH, and an endosomal membrance disruption.
authors.affiliation: Department of Pharmaceutics, University of Utah, Salt Lake City, UT 84108, USA.
authors.forename: Dongin
authors.initials: D
authors.lastname: Kim
authors.forename: Eun Seong
authors.initials: ES
authors.lastname: Lee
authors.forename: Kyung Taek
authors.initials: KT
authors.lastname: Oh
authors.forename: Zhong Gao
authors.initials: ZG
authors.lastname: Gao
authors.forename: You Han
authors.initials: YH
authors.lastname: Bae
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D004337:Drug Carriers; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D011992:Endosomes / Q000378:metabolism; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D011091:Polyesters; D011092:Polyethylene Glycols; D011506:Proteins; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D004337:Drug Carriers; D058973:Folate Receptors, GPI-Anchored; D008823:Micelles; D011091:Polyesters; D011506:Proteins; D011956:Receptors, Cell Surface; C507888:poly(histidine-co-phenylalanine)-block-poly(ethylene glycol); C534468:poly(lactic acid)-block-polyethylene glycol-folate; D011092:Polyethylene Glycols; D004317:Doxorubicin